General Discussion

Crigler-Najjar syndrome is a rare genetic disorder characterized by elevated levels of bilirubin in the blood (hyperbilirubinemia). Bilirubin is a yellowish waste product that is formed when the liver breaks down old or worn out red blood cells (hemolysis). Individuals with Crigler-Najjar syndrome develop hyperbilirubinemia in the absence of hemolysis. The elevated bilirubin levels occur because affected individuals lack a specific liver enzyme required to break down (metabolize) bilirubin. The hallmark finding of Crigler-Najjar syndrome is persistent yellowing of the skin, mucous membranes and whites of the eyes (jaundice). There are two forms of this disorder: Crigler-Najjar syndrome type I, characterized by a nearly complete lack of enzyme activity and severe symptoms; and Crigler-Najjar syndrome type II, characterized by partial enzyme activity and milder symptoms. Most cases of Crigler-Najjar syndrome are inherited as autosomal recessive traits and are due to errors or disruptions (mutations) of the UGT1 gene located on chromosome 2.

Symptoms

The symptoms of Crigler-Najjar syndrome type I become apparent shortly after birth. Affected infants develop severe, persistent yellowing of the skin, mucous membranes and whites of the eyes (jaundice) and may have pale, clay-colored stools. These symptoms persist after the first 3 weeks of life.

Infants with Crigler-Najjar syndrome type I are at risk for developing kernicterus, also known as bilirubin encephalopathy, within the first month of life. Kernicterus is a potentially life-threatening neurological condition in which toxic levels of bilirubin accumulate in the brain, causing damage to the central nervous system. Early signs of kernicterus may include lack of energy (lethargy), vomiting, fever, and/or unsatisfactory feedings. Other symptoms that may follow include absence of certain reflexes (Moro reflex); mild to severe muscle spasms, including spasms in which the head and heels are bent or arched backward and the body bows forward (opisthotonus); and/or uncontrolled involuntary muscle movements (spasticity). In addition, affected infants may suck or nurse weakly, develop a high-pitched cry, and/or exhibit diminished muscle tone (hypotonia), resulting in abnormal "floppiness."

Kernicterus can result in milder symptoms such as clumsiness, difficulty with fine motor skills and underdevelopment of the enamel of teeth, or it can result in severe complications such as hearing loss, problems with sensory perception, convulsions, and slow, continuous, involuntary, writhing movements (athetosis) of the arms and legs or the entire body. An episode of kernicterus can ultimately result in life-threatening brain damage.

Although kernicterus usually develops early during infancy, in some cases, individuals with Crigler-Najjar syndrome type I may not develop kernicterus until later during childhood or in early adulthood.

Crigler-Najjar syndrome type II is a milder disorder than type I. Affected infants develop jaundice although in some cases, jaundice may not be apparent except during times when an infant is sick (concurrent illness), has not eaten for an extended period of time (prolonged fasting) or is under general anesthesia. Some cases of Crigler-Najjar syndrome type II have not been detected until affect individuals are adults. Kernicterus is rarely associated with Crigler-Najjar syndrome type II, but can occur especially when an affected individual is sick, not eating or under anesthesia.

Causes

Crigler-Najjar syndrome is inherited as an autosomal recessive trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

Researchers have determined that Crigler-Najjar syndrome is caused by mutations to the UGT1 gene located on the long arm (q) of chromosome 2 (2q37). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 2q37" refers to band 37 on the long arm of chromosome 2. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

The UGT1 gene contains instructions for creating (encoding) a liver enzyme known as uridine disphosphate-glucuronosyltransferase (UDPGT). This enzyme is required for the conversion (conjugation) and subsequent excretion of bilirubin from the body.

The symptoms of Crigler-Najjar syndrome occur due to the complete or partial absence of this enzyme, which results in the accumulation of unconjugated bilirubin in the body. Bilirubin is an orange-yellow bile pigment that is mainly a byproduct of the natural breakdown (degeneration) of red blood cells (hemolysis). Bilirubin circulates in the liquid portion of the blood (plasma) in conjunction with a protein called albumin; this is called unconjugated bilirubin, which is not dissolvable in water (water-insoluble). Normally, this unconjugated bilirubin is taken up by the liver cells and, with the help of the UDPGT enzyme, is converted to form water-soluble bilirubin diglucuronide (conjugated bilirubin), which is then excreted in the bile. The bile is stored in the gall bladder and, when called upon, passes into the common bile duct and then into the upper portion of the small intestine (duodenum) and aids in digestion. Most bilirubin is eliminated from the body in the feces. When bilirubin levels increase high enough, it can eventually cross the blood-brain barrier, infiltrating brain tissue and causing the neurological symptoms sometimes associated with Crigler-Najjar syndrome.

Parents of children with Crigler-Najjar syndrome type I may exhibit some defects in bilirubin metabolism; however, they do not display any physical findings of this disorder (as they are heterozygous for the defective UDPGT gene).

Affected Populations

Crigler-Najjar syndrome affects males and females in equal numbers. The incidence is estimated to be 1 in 750,000-1,000,000 people in the general population. Many researchers believed that Crigler-Najjar syndrome often goes undiagnosed or misdiagnosed making it difficult to determine its true frequency in the general population.

Crigler-Najjar syndrome was first recognized in six infants of three families who were blood relatives (consanguineous). These cases were reported in the medical literature in 1952 by Drs. Crigler and Najjar. In 1962, Dr. Arias reported a milder version of this disorder, which is now termed Crigler-Najjar syndrome type II.

Related Disorders

Symptoms of the following disorders can be similar to those of Crigler-Najjar syndrome. Comparisons may be useful for a differential diagnosis.

Gilbert syndrome is an inherited metabolic disorder characterized by a defect in the uptake and clearance of unconjugated bilirubin from the liquid portion of the blood (plasma) by the liver. It is believed that symptoms of this disorder (if any) may result from reduced activity of the UDPGT liver enzyme. Gilbert syndrome is caused by mutations of the same gene that causes Crigler-Najjar syndrome, but affected individuals maintain significant activity of the UDPGT enzyme. Most affected individuals have no symptoms (asymptomatic) or may only exhibit mild yellowing of the skin, mucous membranes, and whites of the eyes (jaundice). Jaundice may not be apparent until adolescence. In some cases, affected individuals may also exhibit a general feeling of discomfort (malaise), sluggishness, and/or abdominal discomfort. Bilirubin levels may increase following stress, exertion, alcohol consumption, fasting, and/or infection. Gilbert syndrome is inherited as an autosomal dominant trait. This disorder is also usually responsive to phenobarbital treatment. (For more information on this disorder, choose "Gilbert" as your search term in the Rare Disease Database.)

Rotor syndrome is an extremely rare inherited metabolic disorder characterized by the presence of excessive bilirubin in the blood (hyperbilirubinemia). It is not known whether hyperbilirubinemia is caused by impaired secretion or storage of bilirubin. In most cases, affected individuals exhibit no symptoms of this disorder (asymptomatic). In some cases, persistent yellowing of the skin, mucous membranes, and whites of the eyes (jaundice) is present. Unlike Crigler-Najjar syndrome, affected individuals have high levels of conjugated bilirubin. Rotor syndrome is thought to be inherited as an autosomal recessive trait.

Dubin-Johnson syndrome is a rare genetic liver disorder characterized by elevated levels of bilirubin in blood (hyperbilirubinemia). Persistent yellowing of the skin, mucous membranes, and whites of the eyes (jaundice) is usually the only symptom and, in most cases, does not appear before puberty. In rare cases, enlargement of the liver or spleen may occur (hepatomegally). Like Rotor syndrome, and unlike Crigler-Najjar syndrome, high levels of conjugated bilirubin characterized this disorder. Dubin-Johnson syndrome is inherited as an autosomal recessive disorder. (For more information, choose "Dubin Johnson" as your search term in the Rare Disease Database.)

Rh disease (isoimmunization) is a rare disorder in which red blood cells from the fetus are not compatible with those of the mother. In Rh disease, red blood cells from the fetus may cross the placenta and enter into the mother's bloodstream during pregnancy. This stimulates maternal antibody formation against these "foreign" blood cells. These antibodies eventually reach the fetus via the placenta and cause destruction of fetal red blood cells (hemolysis), resulting in low levels of circulating red blood cells (anemia) in the fetus. In response, the fetal bone marrow releases immature red blood cells (erythroblasts) into the fetal bloodstream. The hemoglobin from the destroyed red blood cells is broken down into bilirubin, a yellow-orange bile pigment. Bilirubin is cleared from the fetal bloodstream by crossing the placenta into the mother's bloodstream. However, after birth abnormally high levels of bilirubin (hyperbilirubinemia) may accumulate in the newborn's bloodstream and other areas of the body, possibly resulting in jaundice and kernicterus. This disease is now almost non-existent due to the availability of anti-Rh globulin, which prevents isoimmunization. (For more information on this disorder, choose "Rh disease" as your search term in the Rare Disease Database.)

Standard Therapies

Diagnosis
A diagnosis of Crigler-Najjar syndrome may suspected within the first few days of life in infants with persistent jaundice. A diagnosis may be confirmed by a thorough clinical evaluation, characteristic findings, detailed patient history, and specialized testing. For example, in infants with this disorder, blood tests reveal abnormally high levels of unconjugated bilirubin in the absence of increased levels of red blood cell degeneration (hemolysis), as in Rh disease (izoimmunization). In addition, bile analysis reveals no detectable bilirubin glucuronides and urine analysis may demonstrate a lack of bilirubin.

It is important to distinguish Crigler-Najjar syndrome type I and type II. The administration of phenobarbital, a barbiturate, while beneficial to individuals affected with Crigler-Najjar syndrome sype II and Gilbert syndrome, is ineffective for those with Crigler-Najjar syndrome type I. Therefore, failure to respond to this medication is an important indication for differential diagnostic purposes.

Treatment
The treatment of Crigler-Najjar syndrome is directed toward lowering the level of unconjugated bilirubin in the blodd. Early treatment is imperative in Crigler-Najjar syndrome type I to prevent the development of kernicterus during the first few months of life. Because Crigler-Najjar syndrome is milder and responds to phenobarbital, treatment is different.

The mainstay of treatment for Crigler-Najjar syndrome type I is aggressive phototherapy. During this procedure, intense fluorescent light is focused on the bare skin, while the eyes are shielded. This helps to speed up the bilirubin excretion in the skin and aids in its decomposition. As affected individuals age and body mass increases and the skin thickens, phototherapy becomes less effective against preventing kernicterus.

Infections, episodes of fevers, and other types of illnesses should be treated immediately to reduce the risk of an affected individual later developing kernicterus.

Plasmapherersis has been used to rapidly lower bilirubin levels in the blood. Plasmapheresis is a method for removing unwanted substances (toxins, metabolic substances and plasma parts) from the blood. During plasmapheresis, blood is removed from the affected individual and blood cells are separated from plasma. The plasma is then replaced with other human plasma and the blood is transfused into the affected individual.

Liver transplantation is the only definitive treatment for individuals with Crigler-Najjar syndrome type I. Liver transplantation as drawbacks such as cost, limited availability of a donor and the potential of rejection. Some physicians recommend a liver transplant if infants or children with severely elevated levels of unconjugated bilirubin do not respond to other therapy (refractory hyperbilirubinemia) or if there is a progression of neurological symptoms. Other physicians believe that liver transplantation should be performed at an early age as preventive therapy, before brain damage can result from early onset kernicterus.

Crigler-Najjar syndrome type II responds to treatment with phenobarbital. In some cases, during an episode of severe hyperbilirubinemia, individuals with Crigler-Najjar syndrome type II may need phototherapy. Some individuals with Crigler-Najjar syndrome type II may not require any treatment, but should be monitored routinely.

Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.

Investigational Therapies

Research has been conducted as to whether limiting bilirubin production with the use of inhibitors, such as tin-protoporphyrin, may be beneficial in treating individuals with Crigler-Najjar syndrome. More studies are needed to determine the long-term effectiveness and possible side effects of the use of such inhibitors for the treatment this disorder.

Research on inborn errors of metabolism such as Crigler-Najjar syndrome is ongoing. Scientists are studying the causes of these disorders and attempting to design enzyme replacement therapies that may return missing and/or deficient enzymes to the body.

Researchers are studying whether the transplantation of liver cells (hepatocytes) are beneficial as a treatment of Crigler-Najjar syndrome. Because the liver is structurally sound in individuals Crigler-Najjar syndrome, researchers are exploring the possibility that transplanting hepatocytes may provide partial correction of the UDPGT enzyme. More studies are needed to determine the long-term safety and effectiveness of this treatment.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Crigler Najjar Syndrome Resources

(Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder [e.g., jaundice, central nervous system damage, etc.].)

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